Among adults seeking treatment for methamphetamine (MA) dependence there is a high prevalence of Attention Deficit/Hyperactivity Disorder (ADHD). Many studies in MA subjects do not screen for ADHD, thus the synergistic interaction between ADHD and MA dependence has not been systematically examined. The proposed project will employ functional neuroimaging and targeted measures of cognition to assess behavioral and neural impairments in cognitive control associated with both ADHD and MA dependence. The goal is to identify the unique contributions of each clinical disorder as well as a functional signature of ADHD+MA comorbidity. Although there has been research into reward and motivational factors in both ADHD and substance dependence, the role of cognitive control and behavioral regulation is under-investigated. Comorbidity of ADHD and stimulant abuse is of particular interest, as stimulants are a preferred treatment for ADHD. Individuals with ADHD display a wide range of cognitive control deficits; however, the research on behavior modification in stimulant dependence has been less consistent. Cognitive control and behavioral insight are essential to optimal decision making and resisting impulses to engage in risky behaviors (e.g., drug-seeking). This proposal will examine the neural substrates of cognitive control impairments associated with detrimental decision-making in ADHD and MA dependence. Four groups will be studied: 1) Subjects with MA dependence but not ADHD; 2) subjects with MA dependence and ADHD; 3) ADHD subjects without MA dependence and 4) typically developing controls. We will administer a GO/NOGO paradigm manipulated to produce high error rates and will further examine the ability to detect errors and subsequently modify behavior. We will examine behavioral modification under situations of increasing working memory load as well as task related neural activity. Our hypothesis is that the group with ADHD and MA dependence (ADHD+MA) will display the most profound impairments in behavior modification and reduced neural activity in lateral prefrontal cortex under conditions of increased memory load. This hypothesis is based on pre-existing compromised functional activity in brain regions subserving working memory in ADHD and stimulant dependence. Results from this proposed study represent an important first step in identifying the neural and behavioral mechanisms of the interaction between substance abuse and ADHD and determining cognitive control impairments in ADHD+MA. Thus the goal of this proposal is consistent with NIDA's strategic plan IV Cross-Cutting Priorities. PUBLIC HEALTH RELEVANCE: The abuse of substances such as methamphetamine represents a major public health concern. Clinical disorders such as ADHD may put individuals at an increased risk for substance dependence; yet little is known about the neural and cognitive impairments associated with ADHD and substance dependence comorbidity. This project will use functional neuroimaging and targeted measures of cognition to investigate impairments in performance monitoring in ADHD and methamphetamine dependence as well as the interaction between the two disorders. Results will provide valuable insight into impaired decision-making in MA dependence but also the synergistic interaction between ADHD and MA dependence.